Herpes simplex virus and varicella zoster virus, the house guests who never leave

HSV encodes six immediate early proteins, five of which regulate gene expression, while VZV has only three reported IE genes. Both viruses encode an immediate early regulated transcriptional transactivator, (HSV-1 ICP4 and VZV ORF62) that is critical to virus replication [6, 7] and shares sufficient functional similarity to enable VZV ORF62 to complement mutants of HSV-1 ICP4 [8, 9]. However, VZV IE62 is a major virion tegument structural protein, while ICP4 is a minor virion protein [10]. The VZV ORF62 protein modulates the IFN response through alteration of the IFN signaling protein IRF3, an activity not yet reported for ICP4 [11]. While both viruses encode a protein with RNA post transcriptional processing activities (HSV-1 ICP27 and VZV ORF 4), the VZV ORF4 cannot complement HSV-1 ICP27 mutants [12]. In addition, both viruses encode proteins with E3 ubiquitin ligase activity (VZV ORF61 and HSV ICP0). However, HSV ICP0 disrupts ND10 bodies by degrading the ND10 components PML and SP100 and blocks IFN-γ signaling [13], whereas VZV ORF61 only partly modifies PML, does not fully disrupt ND10 bodies, and blocks IFN signaling less efficiently. Finally, VZV has no ortholog to the immune evasion ICP47, which modulates surface MHC-I antigen presentation for CD8 + T cell recognition [14].

The biggest difference in genomic organization of the two viruses lies in the short unique region, where VZV has only four proteins and HSV has 12. VZV lacks an equivalent to HSV-1 gD, which is found in all alpherpherpesviruses except VZV and its close cousin, simian varicella virus (SVV). gD is the HSV-1 receptor binding entry mediator, and binds the cellular receptors Herpesvirus entry mediator 1 and 2 (HVEM-1, HVEM 2) and Nectin-1 [15]. The obvious question is what mediates VZV cell binding and entry? This function is attributed to VZV gE, the most abundant VZV glycoprotein. Unlike the minor HSV-1 gE, VZV gE is essential for VZV infectivity. It has a novel specific N terminal domain that is important for binding to a VZV receptor, insulin degrading enzyme (ISG) [16‐18]. While gE interacts with gI in both viruses, VZV gI is particularly critical in VZV neuroptropism [19, 20].

Both viruses encode many virion tegument proteins. A key illustrative divergence involves the cluster of 4 virion tegument proteins encoded by VZV ORFs 9–12 and HSV UL46-49. The HSV UL48 protein (also known as VP16), boosts IE gene expression by recruiting the host cell factors OCT1 and HCF to IE promoters, but is also critical for HSV-1 assembly and egress. In contrast, the VZV equivalent encoded by ORF10 is not needed for VZV IE gene expression or even for VZV growth in culture [21]. In contrast, HSV UL49 is not required for viral replication in culture whereas its VZV homolog (encoded by ORF9) is essential to VZV growth [22]. It is important to note that “non-essential” proteins are usually required for viral infection of organized tissues and animals models for each virus [23].

The innate immune system plays a critical role in controlling HSV-1 and VZV during the early stages of infection. Upon contact with an epithelial surface, the host recognizes pathogen-associated molecular patterns (PAMP) on the virus. Notable among these is the toll-like receptor (TLR) family, with an important role in activating innate immunity. The TLRs promote production of cytokines and other immunoregulatory molecules through intracellular signaling pathways, many employing the adaptor molecule MyD88, leading to nuclear translocation of nuclear factor (NF)-κB and transcription of genes encoding proinflammatory cytokines. TLR-2 and TLR-9 appear to be primarily responsible for recognition of HSV. Although the involvement of TLR in response to VZV is not well characterized, both type I and type II interferons are present in plasma of patients during the early incubation period when viral replication is thought to be mai contained primarily by innate immunity. Recent work has established an important role for TLR3 in preventing HSV induced encephalitis [31]. Given the similarity between HSV and VZV the involvement of TLR-2, -3, and −9 in controlling VZV is likely, but remains to be established.

The importance of interferons in combating both HSV and VZV infections is well established. HSV-1 infection of mice that are deficient in the interferon α/β and γ receptors, or in the signal transduction and transcription factor 1 (Stat1) are highly susceptible to disseminated HSV-1 infections [24, 25]. Treatment of VZV infected SCID-hu mice with antibody to IFN-α/β results in a 10 fold increase in viral replication [32], mirroring the enhanced clearance of virus in immunocompromised children by type I interferon administration [33]. Plasmacytoid dendritic cells (pDC) are an important source of type I interferon during HSV-1 infections and are also attracted to VZV lesions, but in the latter case their capacity to produce type I interferon appears to be inhibited by VZV [28]. Nitric Oxide (NO) is another important effector molecule used by the innate immune system to combat HSV infections. Macrophages and inflammatory monocytes produce NO when infected with HSV in the presence of IFN-γ and TNF-α, and inhibition of NO increases HSV replication [34, 35]. Finally, a novel innate defense mechanism recently reported for VZV is PML cages, which trap VZV nucleocapsids in some cell types. Of interest is that VZV does not degrade PML, as does is the case with HSV-1 [36].

The HSV-1 murine model has enabled considerable assessments of the development of cellular immunity to infection. Following infection, dendritic cells (DC) carry HSV-1 to the draining lymph nodes for activation of CD4⁺ and CD8⁺ T cells. However, recent studies have established that initial expansion of HSV-specific CD8⁺ T cells in the draining lymph nodes of mice is induced by both lymph node resident CD8α⁺ DCs and by migratory DCs from the dermis [37‐41]. Presumably the CD8α⁺ DCs cross-present viral antigens acquired from migratory DCs that originated at the site of infection or acquired from small amounts of free virus that reaches the lymph nodes through lymphatic vessels [42]. Both mature and immature DCs are susceptible to HSV infection [43‐45], but only immature DCs support a productive infection and this leads to apoptosis [46]. HSV Infection of mature DCs results in an abortive infection in which HSV-1 α, β, and γ1 genes are expressed, but no infectious virions are produced [47]. VZV productively infects both immature and mature human DCs, and both HSV-1 and VZV infection of mature DC results in down-regulation of expression of MHC II and several costimulatory molecules resulting in impaired T cell stimulatory capacity [30, 48]. Thus, DCs that are directly infected with either HSV-1 or VZV or those that phagocytose infected cells at the site of infection likely transport viral proteins to the regional lymph nodes. Those, that are directly infected would be inefficient at presenting them to T cells. HSV-specific CD4⁺ and CD8⁺ T cells are expanded following infection, and both populations invade infected skin and contribute to viral clearance [49]. Productive infection and immune evasion in DCs might play a role in the VZV viremic phase, either directly or by transfer to T cells in lymph nodes [29].

HSV and VZV elicit a broad humoral response during infection. Antibodies are directed at viral glycoproteins, tegument or capsid proteins as well as other proteins [50, 51]. These antibodies can neutralize the viruses. With VZV specific antibodies being more effective HSV elicits antibody responses including IgA and IgG [52]. VZV also elicits an antibody response including IgA, IgG, and IgM [53, 54]. VZV specific IgG can be used to treat high-risk patients. HSV specific antibodies have been implicated in protection, but patients with lower antibody titers reactivate less, whereas people with higher levels of antibodies tend to reactivate more frequently [55, 56].

Both viruses have evolved immune evasion mechanisms capable of blunting protective innate and adaptive immunity, which are thought to facilitate development of recurrent disease in the face of a robust immune response. The best characterized immune evasion molecule is the HSV immediate early protein ICP47 that binds to the Transporters A associated with Antigen Processing (TAPs) to inhibit peptide transport into the endoplasmic reticulum for loading onto MHC class I proteins. ICP47 presumably limits CD8⁺ T cell recognition of HSV infected cells, since the CD8⁺ T cell receptor can only recognize peptides bound to MHC class I. However the degree to which ICP47 activity contributes to pathogenesis is not clear. Even latently infected neurons with little HSV antigen or MHC I expression are clearly visible to CD8⁺ T cells since ganglionic CD8⁺ T cells display an activated phenotype in both mice and humans [57, 58]. Moreover, CD8 + T cells can block HSV-1 reactivation from latency in mice and appear to play a major role in control of HSV-2 in the human genital tract [59]. This suggests that the effect of ICP47 can easily be overcome at sites of infection. Since IFN-γ can overcome the block of TAPs by ICP47, rapid IFN-γ production by NK cells at sites of infection might enhance recognition of infected cells by CD8⁺ T cells. VZV does not have an ICP47 homolog and indeed, does not block TAP peptide transport activity [60]. VZV does modulate surface expression of both MHC-I and MHC-II, with MHC-I being modulated in part by the ORF66 kinase [61, 62]. HSV-1 also inhibits innate immunity through: (1) the virion host shut off protein, ICP0 and γ34.5, which inhibit type I interferon-mediated responses in infected cells; (2) glycoprotein C binding and inactivation of of C3b component of complement [63]; (3) an Fc binding ability of gE; and (4) through ICP22, Us5, Us3, and LAT, inhibition of NK cell and CD8 T cell apoptosis of HSV-1 infected cells [64]. VZV modulates IFN signaling, partly through the activity of the IE62 protein, which blocks IRF3 nuclear translocation [11]. The VZV IE63 also modulates IFN responses [65] and inhibits apoptosis [66]. VZV also blocks the NFkB signaling pathway in dendritic cells through activity of VZV ORF61 [67].